1. Field of the Invention
The present invention relates to a human soluble RAGE (receptor for advanced glycation endproducts) polypeptide, specifically to a native soluble RAGE polypeptide having a characteristic C terminal sequence, a nucleic acid encoding the polypeptide, a recombinant vector containing the nucleic acid, and a transformed cell, as well as use of them including screening, assay, diagnosis and treatment.
2. Description of the Related Art
Recently, the number of diabetic patients in Japan is steadily increasing, and according to the statistics published in 1998 by the Ministry of Health and Welfare of Japanese Government, the number of diabetic patients was estimated to be six millions and nine hundreds of thousands, and if sub-clinical patients were included, the number would amount to 14 millions. The factor that directly affects life duration and quality of life of a diabetic patient is systemic derangement in the vascular system secondarily caused by hyperglycemia (i.e. vascular complications), not primary malfunction resulting from deficiency in the insulin supply. In view of this, the mechanism involved in occurrence of such vascular complications should be elucidated and a strategy to conquer such complications based on the knowledge should be constructed, as these are significant problems which need urgent resolution.
The present inventors have been studied on the environmental and genetic factors involved in the development and progression of diabetic complications. The inventors performed in-vitro experiments on cultured vascular cells as well as in-vivo experiments on transgenic animals. Through such experiments, the inventors demonstrated that the environmental factors are mainly accounted for by advanced glycation endproducts (AGE), which increasingly accumulate with the development of diabetes. Moreover, the inventors demonstrated that the genetic factors are significantly related to the genes encoding RAGE which specifically recognize and bind to AGE, as well as genes existing downstream thereof encoding signal molecules and effector molecules(J. Biol. Chem., 272, 8723-8730, 1997; 275, 27781-25790, 2000; and J. Clin. Invest., 108, 261-268, 2001).
It has been predicted that there may be a genetic factor responsible for the susceptibility/resistance of vascular complications in diabetic patients, but identification of such a factor has not been performed yet.
It has been suggested that AGE are involved in the development of complications associated with diabetes and aging. Indeed, it was demonstrated that AGE bind to the receptors present on the surface of monocytes/macrophages, neurons, smooth muscle cells and vascular endothelial cells. It is thought that AGE interacts with these receptors, thereby exerting various physiological and biological actions to the living organisms and cells. For example, AGE act to enhance proliferation of vascular endothelial cells, and in addition, AGE are involved in enhancement of vascular permeability, and of formation of thrombus. As to effect of AGE on monocytes/macrophages, the release of cytokines from those cells would be enhanced, and release of various factors involved in cell proliferation and migration and synthesis of matrix would be also increased. It is further suspected that AGE might be involved in the inflammatory response observed in the wall of vessels.